CJASN ePress. Published on October 11, 2006 as doi: 10.2215/CJN.00160106 Original Articles

Successful Long-Term Treatment of Hyponatremia in Syndrome of Inappropriate Antidiuretic Hormone Secretion with Satavaptan (SR121463B), an Orally Active Nonpeptide

Vasopressin V2-Receptor Antagonist ʈ Alain Soupart,*† Peter Gross,‡ Jean-Jacques Legros,§ Sa´ndor Alfo¨ldi, Djillali Annane,¶ Hassan M. Heshmati,†† and Guy Decaux† ** *Department of Internal Medicine, Jolimont/Tubize-Nivelles Hospital, Tubize, †Research Unit for the Study of Hydromineral Metabolism and **Department of General Internal Medicine, Erasmus University Hospital, Free University of Brussels, Brussels, and §Department of Internal Medicine, Regional Hospital Center of Citadelle, Liege, Belgium; ‡Nephrology, ʈ Department of Medicine, University Medical Center Care Gustav Carus, Dresden, Germany; Szent Imre Ko´rha´z e´s Rendelo¨inte´zet I, Belgyo´gya´szati Oszta´ly, Budapest, Hungary; ¶Department of Intensive Care Unit, Raymond Poincare Hospital, Garches, France; and ††Clinical Development, Sanofi-Aventis, Malvern, Pennsylvania

The effects of satavaptan (SR121463B), a novel long-acting orally active vasopressin V2-receptor antagonist, were investigated in patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In the first part of this randomized, double-blind study, 34 patients first were treated with satavaptan (versus placebo) for up to 5 d and then during 23 d of open-label dosage-adjustment period. In the second part of the study, long-term efficacy and safety of satavaptan was assessed in an open-label trial during at least 12 mo. Mean (؎SD) serum sodium (SNa) levels before treatment were 127 ؎ 2 mmol/L Responders (patients SNa levels .(12 ؍ and 127 ؎ 5 mmol/L (50 mg, n ,(14 ؍ mmol/L (25 mg, n 6 ؎ 125 ,(8 ؍ placebo, n) normalized or increased by at least 5 mmol/L from baseline during the double-blind period) were 79% in the 25-mg group (SNa ؎ and 13% in the placebo group (SNa 130 ,(0.005 ؍ in the 50-mg group (SNa 140 ؎ 6 mmol/L; P %83 ,(0.006 ؍ mmol/L; P 3 ؎ 136 5 mmol/L). No drug-related serious adverse events were recorded. During the long-term treatment, 15 of 18 enrolled patients achieved 6 mo and 10 achieved 12 mo of treatment. The SNa response was maintained during this time with a good tolerance.

The new oral vasopressin V2-receptor antagonist satavaptan adequately corrects mild or moderate hyponatremia in patients with SIADH and has a good safety profile. Clin J Am Soc Nephrol 1: 634–640, 2006. doi: 10.2215/CJN.00160106

asopressin is involved in most cases of sustained hy- origins. After the initial phase of the study (short-term, 1 mo), ponatremia (1). Therefore, the use of specific blockers we evaluated for the first time the efficacy and the tolerance of of vasopressin receptors is a logical approach in the aVRA over a long-term period (12 mo). V 2 treatment of patients with syndrome of inappropriate antidi- uretic hormone secretion (SIADH) and may present advantages over current available therapies (2). Selective nonpeptide V - Materials and Methods 2 Patients receptor antagonists (V RA) have been in development since 2 From June 2001 to June 2003, a total of 35 patients from four countries 1992 (3–6). Oral compounds have been synthesized more re- (Belgium, Germany, Hungary, and France) were included in a random- cently, and, to our knowledge, publications have focused ized, double-blind, placebo-controlled study to assess the efficacy and mainly on patients with SIADH that is treated with an oral the safety of different dosages of satavaptan in SIADH. The diagnosis Ͻ V2RA for a short period of time ( 1 wk) (7–10). of SIADH was based on several criteria: True serum hypo-osmolality; In this study, we investigated the efficacy and the safety of a inappropriate urinary osmolality; clinical euvolemia; elevated urinary new oral nonpeptide V2RA, satavaptan (SR121463B) (11), in sodium excretion while on a normal salt and water intake; and normal correcting hyponatremia in patients with SIADH of various renal, adrenal, and thyroid functions. Patients with low sodium excre- tion (Յ20 mmol/L) as a result of low solute intake (anorexia) were included. Drug-induced SIADH was limited to carbamazepine and Received January 13, 2006. Accepted August 21, 2006. antidepressants. The search for the cause of SIADH (especially neopla- Published online ahead of print. Publication date available at www.cjasn.org. sia and iatrogenic) was performed carefully by each investigator before considering the origin as idiopathic. Address correspondence to: Dr. Alain Soupart, Research Unit for the Study of Inclusion criteria were age 18 yr or older, stable hyponatremia (se- Hydromineral Metabolism, Department of General Internal Medicine, Free Uni- Յ versity of Brussels, Hoˆpital Erasme, 808, route de Lennik, 1070 Brussels, Belgium. rum sodium [SNa] increase 4 mmol/L between two measurements of Phone: ϩ322-555-4960; Fax: ϩ322-555-3211; E-mail: [email protected] 24 h apart) between 115 and 132 mmol/L during the screening period,

Copyright © 2006 by the American Society of Nephrology ISSN: 1555-9041/106-0634 Clin J Am Soc Nephrol 1: 634–640, 2006 Treatment of SIADH with Vasopressin V2RA 635 ability to give a written informed consent, and ability to follow verbal chromatography tandem mass spectrometry (Department of Sanofi- and written instructions. Exclusion criteria were cardiac failure, symp- Synthelabo Research, Malvern, PA). Urine samples were collected daily tomatic liver disease or serum alanine aminotransferase or aspartate (collections from 8 a.m. to 2 p.m., and from 2 p.m. to 8 a.m.) for urinary aminotransferase more than two-fold the upper limit of normal, un- volume, electrolyte, and osmolality determinations. controlled diabetes (blood glucose Ն200 mg/dl), significant renal im- Free water clearance (FWC) was calculated using the following for- pairment (serum creatinine Ͼ150 ␮mol/L), inadequate hematologic mula: (urinary flow rate) ϫ (1 Ϫ urinary osmolality/serum osmolality). function (hemoglobin Ͻ9 g/dl, neutrophils Ͻ1500/mm3, platelets Effective FWC (EFWC) was calculated using the following formula: Ͻ100,000/mm3), and hypothyroidism or adrenal deficiency. Radiother- (urinary flow rate) ϫ (1 Ϫ urinary sodium ϩ potassium/SNa). apy and chemotherapy within 2 wk before study drug administration Written informed consent was obtained from each patient. The study were not allowed. Previous and concomitant administration of some protocol was approved by the local ethics committee of the participat- drugs were not accepted (from 1 mo before the randomization for ing centers. demeclocycline or lithium and 2 d for diuretics and urea). Women who were of childbearing potential and had positive pregnancy test and Statistical Analyses women with absence of medically approved contraceptive methods Data are provided as mean Ϯ SD or SEM as appropriate. All statis- were excluded. tical tests were two sided at the 5% significance level. Comparison of data between treatment groups was done by using ANOVA for con- Protocol tinuous data and Fisher exact test for qualitative variables. In the first part of the study (1 mo), after a screening period (day Ϫ6 to day Ϫ1) to confirm stable hyponatremia, patients were randomly assigned to take placebo or a once-daily dose of 25 or 50 mg of Results satavaptan during a double-blind period of up to 5 d. The duration of Short-Term Study (First Part) the double-blind period could have been Ͻ5 d if SNa reached values In the double-blind phase, nine patients received placebo, 14 Ն135 mmol/L on two consecutive days before day 5. Patients were patients received 25 mg/d, and 12 patients received 50 mg/d of hospitalized during the double-blind period. The double-blind period satavaptan. Thirty-four patients completed the double-blind was followed by 23 d of open-label treatment (dosage adjustment). In portion of the study. One patient in the placebo group discon- the initial dosage adjustment on day 6, if the last SNa on day 5 was tinued the treatment on the second day because of an adverse Ͻ135 mmol/L, then patients received a dosage of satavaptan equal to event. Twenty-two patients completed the open-label portion Ն the dosage of their group. If SNa was 135 mmol/L, then they received of the study. Thirteen patients discontinued the open-label a dosage that was one level below the dosage of their group (in case of period for various reasons (e.g., adverse event, death, lack of 25 mg, the drug was discontinued). From day 7 to the end of the efficacy, personal reason). open-label period, the dosage was adjusted on the basis of the results of There were no significant differences in the baseline charac- SNa. In the second part of the study (12 mo), the long-term efficacy and the safety of the satavaptan were assessed in an open-label trial with teristics of the patients between groups (Table 1). In the patients 12.5, 25, or 50 mg once daily. with drug-induced SIADH, all cases were related to carbamaz- Drug was administered in the morning under fasting conditions. epine that was prescribed for epilepsy or chronic pain (the drug During the entire study, it was recommended to limit total fluid intake was continued during the study). Patients presented with mod- to 1500 ml/d. Dietary sodium intake remained unchanged throughout erate hyponatremia (range 114 to 131 mmol/L). The low uri- the study for each patient. nary sodium that was observed in some patients may be attrib- Treatment aim was to obtain normalization of the SNa within a range uted to the low caloric and solute intake of the patients. of 135 to 145 mmol/L on two separate consecutive determinations. Efficacy. Figure 1 represents the course of the SNa Responders were patients who reached normal SNa levels or increasing throughout the double-blind period. SNa reached 136 Ϯ 3 SNa levels by at least 5 mmol/L from baseline over at least 24 h during mmol/L (n ϭ 14; range 131 to 141 mmol/L) in the 25-mg group the double-blind period. (P ϭ 0.011 versus placebo), 140 Ϯ 6 mmol/L (n ϭ 12; range 133 Body weight was assessed each day during the double-blind period Ͻ before dosing and on days 6, 7, 10, 14, 21, and 28 in the open-label to 156 mmol/L) in the 50-mg group (P 0.0001 versus placebo), Ϯ ϭ period. Vital signs, including supine and standing systolic and diastolic and 130 5 mmol/L (n 8; range 120 to 134 mmol/L) in the BP, heart rate, and oral temperature, were assessed three times per day placebo group. There was a trend for a higher increase in SNa from day 1 to day 7 and once a day thereafter (just before dosing). in the 50-mg group (dosage-related effect). Serum osmolality Thirst index was evaluated by a visual analogue scale each day of the also was significantly higher at the end of the double-blind double-blind period and on days 6, 7, 10, 14, 21, and 28 of the open- period in the treated patients compared with placebo (data not label period (7). Electrocardiogram (standard 12-lead) was recorded at shown). screening and on days 5, 14, and 28, before dosing. A total of nine patients who were treated with satavaptan Blood samples for SNa and osmolality measurements were collected (five in the 25-mg group and four in the 50-mg group) pre- between 7 and 9 a.m. on fasting patients before and 6 and 12 h after sented with an increase in SNa concentration Ͼ8 mmol/L drug intake each day during the double-blind period and before drug within 24 h after the first dose. The increase in SNa ranged from intake at each visit of the open-label period. Blood samples also were 9 to 16 mmol/L. Per protocol, to avoid brain myelinolysis, the collected on screening day and on days 5, 14, and 28 before dosing for standard hematology and serum chemistry. rate of correction of SNa should not exceed 12 mmol/L during For arginine vasopressin, renin, and aldosterone, blood samples were the first 24 h and 18 mmol/L during the first 48 h. In three taken at the same time from patients in the supine position for at least patients (two in the 25-mg group and one in the 50-mg group), 30 min. Plasma satavaptan concentration was determined just before the increase was Ͼ12 mmol/L per 24 h (14 to 16 mmol/L per drug intake and 3, 6, and 12 h after by use of a validated liquid 24 h). In the 25-mg group, the mean gradient of increase was 7 636 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 1: 634–640, 2006

Table 1. Summary of demographic data and of disease characteristics at baselinea

Satavaptan Characteristics Placebo (n ϭ 9) 25 mg (n ϭ 14) 50 mg (n ϭ 12)

Age (yr) mean Ϯ SD 62.0 Ϯ 18.9 71.1 Ϯ 10.8 68.9 Ϯ 14.0 range 34 to 85 55 to 93 45 to 96 Gender (male/female) 2/7 7/7 4/8 SIADH origin (n ͓%͔) malignant tumor 1 (11.1) 2 (14.3) 2 (16.7) carbamazepine 2 (22.2) 3 (21.4) 2 (16.7) miscellaneous 3 (33.3) 4 (28.6) 3 (25.0) idiopathic 3 (33.3) 5 (35.7) 5 (41.7) SNa (mmol/L) mean Ϯ SD 126 Ϯ 3 125 Ϯ 6 127 Ϯ 5 range 120 to 130 114 to 131 115 to 131 Serum creatinine (␮mol/L) mean Ϯ SD 64.4 Ϯ 23.0 74.3 Ϯ 19.9 55.0 Ϯ 14.5 range 40.0 to 120.0 40.0 to 100.0 30.0 to 70.0 Blood urea nitrogen (mmol/L) mean Ϯ SD 3.9 Ϯ 2.4 4.5 Ϯ 2.5 4.2 Ϯ 1.4 range 1.4 to 8.5 2.0 to 10.5 2.0 to 5.9 Serum uric acid (␮mol/L) mean Ϯ SD 158 Ϯ 63 214 Ϯ 132 170 Ϯ 53 range 80 to 270 80 to 580 100 to 270

Serum osmolality (mOsm/kg H2O) mean Ϯ SD 257 Ϯ 10 258 Ϯ 14 264 Ϯ 12 range 237 to 270 230 to 277 241 to 284 Urinary sodium (mmol/L) mean Ϯ SD 69 Ϯ 36 45 Ϯ 27 77 Ϯ 64 range 19 to 124 11 to 103 6 to 176 Urinary potassium (mmol/L) mean Ϯ SD 27 Ϯ 15 28 Ϯ 18 31 Ϯ 24 range 10 to 60 9 to 72 4 to 74

Urinary osmolality (mOsm/kg H2O) mean Ϯ SD 428 Ϯ 198 432 Ϯ 168 451 Ϯ 206 range 184 to 848 257 to 794 187 to 657

aSIADH, syndrome of inappropriate antidiuretic hormone secretion; SNa, serum sodium. mmol/L during the first 24 h (5 mmol/L after the first 6 h). In were significantly correlated to trough plasma satavaptan con- the 50-mg group, the mean gradient of increase was 6 mmol/L centrations (P Ͻ 0.0001, r ϭ 0.694). The correlation remained during the first 24 h (4 mmol/L after the first 6 h). Also, one statistically significant (but weaker) when one outlier patient patient (50-mg group) had an increase in SNa Ͼ18 mmol/L with high SNa (156 mmol/L) was removed from the analysis within 48 h (increase of 19 mmol/L). (P ϭ 0.038, r ϭ 0.243). For both dosages, a large interindividual The number of responders at the end of the double-blind variability was observed in plasma satavaptan concentrations. period was significantly higher in both satavaptan groups com- Maximal concentrations were observed 3 h after dosing, and pared with placebo. Responders were 79% (11 of 14 patients) in mean plasma concentrations increased with dosage and dura- the 25-mg group (P ϭ 0.006 versus placebo), 83% (10 of 12 tion of administration with stabilization on day 5 (data not patients) in the 50-mg group (P ϭ 0.005 versus placebo), and shown). Overall, plasma satavaptan concentrations were lower 13% (one of eight patients) in the placebo group. For responder in nonresponders than in responders. A decrease in exposure to patients, the median time to reach response in SNa levels was satavaptan was observed in patients who received carbamaz- significantly lower in the 25-mg group (63 h; P ϭ 0.010) and the epine, a widely known CYP3A inducer. Among the five non- 50-mg group (30 h; P ϭ 0.002) in comparison with the placebo responders who were on active treatment, two patients (one in group (Ͼ120 h). the 25-mg group and one in the 50-mg group) received carbam- At the end of the double-blind period, SNa concentrations azepine during the study. However, three patients who were Clin J Am Soc Nephrol 1: 634–640, 2006 Treatment of SIADH with Vasopressin V2RA 637

Figure 1. Mean (ϮSEM) serum sodium (SNa; mmol/L) during the double-blind period in the placebo, 25-mg, and 50-mg groups (*P Ͻ 0.05; **P Ͻ 0.01; ***P Ͻ 0.001). on carbamazepine were responders (two in the 25-mg group and one in the 50-mg group). In three nonresponders, the lack of increase in SNa despite a large increase in diuresis and a Ϯ decrease in urinary osmolality probably was due to an increase Figure 2. Mean ( SEM) free water clearance (FWC; ml/h, 0 to in water intake (likely patients with “reset osmostat”). 6 h postdose) during the double-blind period in the placebo, Ͻ Ͻ Ͻ At the end of the double-blind period, the 6-h postdose 25-mg, and 50-mg groups (*P 0.05; **P 0.01; ***P 0.001). diuresis was increased by 573 Ϯ 423 ml in the 25-mg group (P ϭ 0.002 versus placebo), 488 Ϯ 392 ml in the 50-mg group (P ϭ 0.009 versus placebo), and 10 Ϯ 179 ml in the placebo group. At the end of the double-blind period, the 6-h postdose urinary Ϯ osmolality was 225 100 mOsm/kg H2O in the 25-mg group, Ϯ Ϯ 179 112 mOsm/kg H2O in the 50-mg group, and 350 160 mOsm/kg H2O in the placebo group. The decrease was signif- icant in the 50-mg group (P ϭ 0.044 versus placebo). The 6-h postdose urinary electrolyte excretion (sodium and potassium) was not significantly modified by satavaptan. Figure 2 shows the 6-h postdose FWC in the three groups during the double-blind period. It was increased from baseline in a dosage-related manner in the satavaptan groups. A peak was observed the first day. Mean change from baseline at the end of the double-blind period was significantly higher for the 50-mg dose (P ϭ 0.008 versus placebo) and close to significance for the 25-mg dose (P ϭ 0.058 versus placebo). A very similar pattern was observed for EFWC (Figure 3). At the end of the double-blind period, there was no signifi- cant change from baseline in body weight, thirst index, fluid Figure 3. Mean (ϮSEM) effective free water clearance (EFWC; intake, plasma arginine vasopressin, plasma renin, and serum ml/h, 0 to 6 h postdose) during the double-blind period in the aldosterone in both satavaptan-treated groups compared with placebo, 25-mg, and 50-mg groups (*P Ͻ 0.05; **P Ͻ 0.01; ***P Ͻ placebo (Table 2). For body weight, a trend for a higher de- 0.001). crease versus placebo was observed at 24 h postdose in the 50-mg group. During the open-label adjustment period, mean SNa re- double-blind period, a moderate decrease in standing systolic mained in the normal range (SNa 137 Ϯ 4 mmol/L at the end and diastolic BP was observed in the 50-mg group compared of the open-label), whereas the majority of the patients (27 with placebo (decrease of 6 Ϯ 23 mmHg versus increase of 2 Ϯ [79%] of 34 double-blind completer patients) received 25 mg/d 12 mmHg and decrease of 8 Ϯ 14 mmHg versus decrease of 4 Ϯ of the compound. 12 mmHg, respectively). No other clinically relevant changes Safety. No clinically relevant changes were observed for were observed in supine BP in the 50-mg group or in supine or respiratory rate and oral temperature. For BP, at the end of the standing BP in the 25-mg group, compared with placebo. Or- 638 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 1: 634–640, 2006

Table 2. Changes from baseline in body weight, thirst index, fluid intake, AVP, renin, and aldosterone at the end of the double-blind perioda

Satavaptan Parameters Placebo (n ϭ 8) 25 mg (n ϭ 14) 50 mg (n ϭ 12)

Body weight (kg) baseline (mean Ϯ SD) 60.6 Ϯ 9.9 59.5 Ϯ 12.4 56.9 Ϯ 12.5 change from baseline (mean Ϯ SD) Ϫ1.2 Ϯ 2.0 Ϫ0.4 Ϯ 1.4 Ϫ1.3 Ϯ 1.7 P value (versus placebo) — 0.298 0.930 Thirst index (mm) baseline (mean Ϯ SD) 51 Ϯ 25 50 Ϯ 14 56 Ϯ 13 change from baseline (mean Ϯ SD) Ϫ3 Ϯ 24 4 Ϯ 17 6 Ϯ 30 P value (versus placebo) — 0.534 0.466 Fluid intake (ml/24 h) baseline (mean Ϯ SD) 1570 Ϯ 612 1558 Ϯ 551 1539 Ϯ 925 change from baseline (mean Ϯ SD) Ϫ211 Ϯ 550 Ϫ113 Ϯ 706 275 Ϯ 926 P value (versus placebo) — 0.776 0.185 AVP (ng/L) baseline (mean Ϯ SD) 1.5 Ϯ 1.9 1.4 Ϯ 2.2 3.6 Ϯ 9.1 change from baseline (mean Ϯ SD) Ϫ0.7 Ϯ 1.3 1.0 Ϯ 1.7 2.6 Ϯ 6.7 P value (versus placebo) — 0.391 0.100 Renin (ng/ml per h) baseline (mean Ϯ SD) 0.6 Ϯ 0.6 0.9 Ϯ 1.1 1.7 Ϯ 4.4 change from baseline (mean Ϯ SD) 0.4 Ϯ 0.7 0.3 Ϯ 1.4 0.5 Ϯ 3.1 P value (versus placebo) — 0.966 0.932 Aldosterone (ng/L) baseline (mean Ϯ SD) 144 Ϯ 158 93 Ϯ 79 65 Ϯ 66 change from baseline (mean Ϯ SD) Ϫ31 Ϯ 54 14 Ϯ 145 Ϫ2 Ϯ 68 P value (versus placebo) — 0.344 0.554

aAVP, arginine vasopressin. thostatic hypotension (systolic BP standing Ϫ supine ՅϪ20 Table 3. Adverse event distribution during the double- mmHg) was observed in eight (67%) patients in the 25-mg blind period group, five (50%) patients in the 50-mg group, and four (44%) Satavaptan patients in the placebo group during the double-blind period. Adverse Events Placebo Electrocardiogram at the end of the double-blind period (n ϭ 9) 25 mg 50 mg showed an increase in mean heart rate from baseline in the (n ϭ 14) (n ϭ 12) 25-mg group (6 Ϯ 14 bpm) and in the placebo group (6 Ϯ 23 bpm) but not in the 50-mg group (decrease of 2 Ϯ 10 bpm). No Urinary tract infection 0 1 1 trend to prolonged QTcB interval (Ͼ450 ms in men and Ͼ470 Vomiting 0 1 0 ms in women) was observed. Pruritus 0 1 0 Stomatitis 1 0 0 During the double-blind period, four (15%) patients who a were treated with satavaptan (in both groups) and two (22%) Vasculitis 10 0 patients who were treated with placebo experienced at least Cryoglobulinemia 1 0 0 one adverse event, including a serious adverse event (Table 3). aSerious adverse event. None of the adverse events was considered by the investigators to be related to study treatment. During the overall exposure to satavaptan (double-blind ϩ open-label treatment), 18 (51%) bronchitis (with recovery), gastrointestinal hemorrhage (lead- patients experienced at least one adverse event, including a ing to death), vasculitis (leading to death), pneumonia (leading serious adverse event. In only one patient were the adverse to death), and malignant brain neoplasm (leading to death). events (polyuria, nausea, moderate rigors, and confusion) con- None of the serious adverse events was considered by the sidered by the investigator to be related to study treatment investigators to be related to study treatment. Overall, three (patient on 25 mg of satavaptan during the open-label period). (9%) patients withdrew from study treatment as a result of Serious adverse events, observed in seven (20%) patients, were serious adverse events (worsening of preexisting vasculitis on sepsis (leading to death), respiratory failure (with recovery), placebo during the double-blind period, gastrointestinal hem- Clin J Am Soc Nephrol 1: 634–640, 2006 Treatment of SIADH with Vasopressin V2RA 639

ϩ orrhage on 25 mg of satavaptan during the open-label period, V1a V2) and oral bioavailability are currently in development and respiratory failure on 25 mg of satavaptan during the (or recently approved): OPC41061 (tolvaptan), VPA985 (lix- ϩ open-label period). ivaptan), and YM087 (conivaptan: V1a V2). Few published Hypernatremia (SNa Ͼ145 mmol/L) developed in two pa- studies with these V2RA have been conducted in patients with tients during the double-blind period (one on 25 mg of sat- cirrhosis (with or without hyponatremia) (7,9,13) and patients avaptan and one on 50 mg of satavaptan) and in five patients with congestive heart failure (with or without hyponatremia) during the open-label period (four on 25 mg of satavaptan and (14,15) showing that these V2RA are effective in increasing one on 50 mg of satavaptan). The SNa values were 146 and 156 FWC in various water-retention disorders. In SIADH, most of mmol/L during the double-blind period (the first patient, who the publications are focused on short-term studies (Ͻ1 wk) was on 25 mg of satavaptan, had vomiting of mild intensity (7–10). In our study, the number of responders to satavaptan at with spontaneous resolution, and the second patient, on 50 mg the end of the double-blind was comparable with both 25-mg of satavaptan, was asymptomatic) and from 146 to 161 mmol/L (79%) and 50-mg (83%) dosages, the lowest SNa observed being during the open-label period (one patient on 25 mg of sat- 131 mmol/L. The normalization of the natremia after oral ad- avaptan with a SNa of 146 mmol/L experienced nausea, rigors, ministration of satavaptan is the result of the rapid and marked and confusion, and the other four patients were asymptomatic). increase in the renal free water excretion. During the first Among the nine patients who had rapid correction of SNa month of treatment, mean SNa remained normal and the ma- during the double-blind period (increase in SNa Ͼ8 mmol/L jority (79%) of the patients were controlled with the dosage of within 24 h after the first dose), one patient experienced vom- 25 mg/d. iting of mild intensity (25 mg of satavaptan). No significant Excessive correction of hyponatremia is a hazardous situa- changes in other laboratory parameters (renal, hepatic, or he- tion with major risks for brain damage (myelinolysis) and matologic testings) were noticed in satavaptan-treated patients neurologic sequelae (16). Careful approach of patients with compared with placebo. sustained hyponatremia implies a limited correction below 12 mmol/L per 24 h (and Ͻ18 mmol/L per 48 h) and even less Long-Term Study (Second Part) than 8 to 10 mmol/L per 24 h for patients with additional risk Eighteen patients (12 women and six men) who initially were factors for myelinolysis (16,17). In our study, the mean daily included in the short-term study (1 mo) were able to be in- increase in SNa was lower than 8 mmol/L in the first 24 h of cluded in this long-term study (at least 12 mo). Mean (ϮSD) age correction with satavaptan. Few patients (n ϭ 3) in the active was 68 Ϯ 14 yr, and the origin of SIADH was malignancy (n ϭ 2), drug (n ϭ 4), miscellaneous (n ϭ 4), and idiopathic (n ϭ 8). treatment group had a correction level above 12 mmol/L per Three dosages of satavaptan were available during this period 24 h (maximum daily increase observed 16 mmol/L per 24 h) (12.5, 25, and 50 mg, administered once daily). The dosage was after the first dose of satavaptan. None of them presented adjusted as a function of the SNa values in patients who were neurologic complications. The maximum SNa increase and on controlled water intake (Յ1500 ml/d). Table 4 shows the aquaresis were observed 3 to 6 h after dosing, but SNa contin- evolution of the SNa during the open-label long-term exten- ued to increase further. Like with the other therapies, excessive sion. correction with V2RA could produce osmotic demyelination Ten patients now are treated for at least 12 mo without drug (18,19). Good control and limited correction are achievable by escape. No adverse event related to satavaptan was noted use of titrated doses of V2RA during the initial phase of cor- during this period. rection, especially in patients with severe hyponatremia (Ͻ115 to 120 mmol/L). Indeed, most of published cases of myelinol- Discussion ysis were reported in patients with initial SNa Ͻ115 mmol/L

This is the first study to use an oral V2RA on a long-term (20), which was not the case in our study. basis to treat patients with SIADH-related hyponatremia. Sat- The efficacy of satavaptan to control the natremia remained avaptan has a great selectivity and high affinity for renal V2 excellent during the entire study period. Under a state of rela- receptors with the advantage of having a long half-life (14 to tive water control (Ͻ1500 ml/d), mean SNa values remained 17 h) (11,12). within the normal range during the open-label period.

Three other compounds with selectivity for V2 receptors (or These encouraging data over the efficacy of satavaptan are

Table 4. Evolution of SNa during the open-label long-term extension

Time (mo) SNa (mmol/L) Baselinea 6812

No. of patients 18 15 13 10 Mean Ϯ SD 135 Ϯ 4 138 Ϯ 3 138 Ϯ 5 140 Ϯ 3 Range 121 to 146 133 to 145 127 to 145 136 to 145

aEnd of short-term (1-mo) study. 640 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 1: 634–640, 2006 strengthened by the good tolerance to the treatment that was center, randomized, placebo-controlled trial. Hepatology 37: observed in our patients. Only a slight increase in thirst was 182–191, 2003 noted in both dosage groups. Some patients regained weight 8. Decaux G: Long-term treatment of patients with inappro- during treatment probably because their general status im- priate secretion of antidiuretic hormone by the vasopressin proved after correction of the hyponatremia, leading to a better receptor antagonist conivaptan, urea, or furosemide. Am J Med 110: 582–584, 2001 food intake. The most frequently observed change in vital signs 9. Decaux G: Difference in solute excretion during correction was orthostatic hypotension, usually asymptomatic and ex- of hyponatremic patients with cirrhosis or syndrome of plained by the aquaretic activity of the compound. Only one inappropriate secretion of antidiuretic hormone by oral patient presented symptoms that potentially were related to the vasopressin V2 receptor antagonist VPA-985. J Lab Clin compound (polyuria, nausea, rigors, and confusion), and no Med 138: 18–21, 2001 patients discontinued the study in relation to the treatment, 10. Ghali JK, Koren MJ, Taylor JR, Brooks-Asplund E, Fan K, even in the patients who were treated for 12 mo. Long WA, Smith N: Efficacy and safety of oral conivaptan. Although evolution of the symptoms related to hyponatre- A V1A/V2 vasopressin receptor antagonist, assessed in a mia was not significantly evaluated in the design of this study, randomized, placebo-controlled trial in patients with patients subjectively felt better when treated with satavaptan. euvolemic or hypervolemic hyponatremia. J Clin Endocri- Additional studies are in progress to evaluate these particular nol Metab 91: 2145–2152, 2006 points. 11. Serradeil-Le Gal C, Lacour C, Valette G, Garcia G, Foulon L, Galindo G, Bankir L, Pouzet B, Guillon G, Barberis C, Chicot D, Jard S, Vilain P, Garcia C, Marty E, Raufaste D, Conclusion Brossard G, Nisato D, Maffrand JP, Le Fur G: Character- Treatment of patients with SIADH and mild or moderate ization of SR121463A, a highly potent and selective orally hyponatremia with satavaptan, a new oral V2RA, corrects SNa active vasopressin V2 receptor antagonist. J Clin Invest 98: with a good safety profile. This effect was confirmed for the 2729–2738, 1996 first time on a long-term basis. 12. Serradeil-Le Gal C: An overview of SR121463, a selective non-peptide vasopressin V2 receptor antagonist. Cardiovasc Acknowledgments Drug Rev 19: 201–214, 2001 The study was sponsored by Sanofi-Aventis. 13. Gerbes AL, Gulberg V, Gines P, Decaux G, Gross P, Gan- This study was designed by H.M.H., G.D., and Dr. J.G. Verbalis. djini H, Djian J; the VPA Study Group: Therapy of hypo- We thank F. Coste for supervising the clinical operations; M. De- natremia in cirrhosis with a vasopressin receptor antago- Ubeda and I. Remoissenet for data collection; S. Turpault for pharma- nist: A randomized double-blind multicenter trial. cokinetics measurements; and C. Smolens, D. Lei, and A. Boddy for Gastroenterology 124: 933–939, 2003 statistical analysis. 14. 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